The incidence and mortality rates of prostate cancer vary substantially amongst different geographic areas and ethnic groups. Most notably, African-American men have the highest risk of developing prostate cancer, and due to the manifestation of a more aggressive disease, they have over twice the mortality rate of European-American men. While socioeconomic factors contribute to this health disparity, they do not fully explain the differences in prostate cancer incidence, aggressiveness, and mortality amongst different race/ethnic groups in the United States. We pursued the hypothesis that the gene expression profiles of prostate tumors from African-American and European-American men may reveal biological differences between the two groups that could explain the more aggressive cancer phenotype in African-American men. Using microarray technology, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. These tumors were matched on clinical parameters. We also evaluated 18 non-tumor prostate tissues from 7 African-American and 11 European-American patients. The resulting datasets were analyzed for expression differences on the gene and pathway level comparing African-American with European-American patients. Our analysis revealed a significant number of genes, e.g., 162 transcripts at a false-discovery rate less than 5%, to be differently expressed between African-American and European-American patients. Using a disease association analysis, we identified a common relationship of these transcripts with autoimmunity and inflammation. These findings were corroborated on the pathway level with numerous differently expressed genes clustering in immune response, stress response, cytokine signaling, and chemotaxis pathways. More specifically, an interferon gene signature was present in tumors of African-Americans patient suggesting the involvement of viral infections in disease pathology. Several known metastasis-promoting genes, including MMP9 and CXCR4, were more highly expressed in tumors from African-Americans than European-Americans. Furthermore, a two-gene tumor signature was identified that accurately differentiated between African-American and European-American patients. This finding was confirmed in a blinded analysis of a second sample set. In conclusion, the gene expression profiles of prostate tumors indicate prominent differences in tumor immunobiology between African-American and European-American men. The profiles portray the existence of a distinct tumor microenvironment in these two patient groups. Because of these findings, we have started two projects exploring the contribution of 1) viral infections and 2) intrinsic expression differences in immunoregulatory genes to the existing prostate cancer health disparity between African-American men and European-American men. In a separate study, we also compared the tumor microRNA signatures between African-Americans and European-Americans. Few microRNAs were differently expressed. MiR-129, miR-196b, and miR-342 were found to be less abundant (20% to 30% lower) in tumors of African-Americans (n = 30) than in tumors of European-Americans (n =30). From our analysis, it did not appear that tumor microRNAs are very differently expressed by race/ethnicity.